Inhibition of NLRP3 Inflammasome Pathway by Butyrate Improves Corneal Wound Healing in Corneal Alkali Burn

Int J Mol Sci. 2017 Mar 5;18(3):562. doi: 10.3390/ijms18030562.


Epithelial cells are involved in the regulation of innate and adaptive immunity in response to different stresses. The purpose of this study was to investigate if alkali-injured corneal epithelia activate innate immunity through the nucleotide-binding oligomerization domain-containing protein (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway. A unilateral alkali burn (AB) was created in the central cornea of C57BL/6 mice. Mice received either no topical treatment or topical treatment with sodium butyrate (NaB), β-hydroxybutyric acid (HBA), dexamethasone (Dex), or vehicle (balanced salt solution, BSS) quater in die (QID) for two or five days (d). We evaluated the expression of inflammasome components including NLRP3, apoptosis-associated speck-like protein (ASC), and caspase-1, as well as the downstream cytokine interleukin (IL)-1β. We found elevation of NLRP3 and IL-1β messenger RNA (mRNA) transcripts, as well as levels of inflammasome component proteins in the alkali-injured corneas compared to naïve corneas. Treatment with NLRP3 inhibitors using NaB and HBA preserved corneal clarity and decreased NLRP3, caspase-1, and IL-1β mRNA transcripts, as well as NLRP3 protein expression on post-injury compared to BSS-treated corneas. These findings identified a novel innate immune signaling pathway activated by AB. Blocking the NLRP3 pathway in AB mouse model decreases inflammation, resulting in greater corneal clarity. These results provide a mechanistic basis for optimizing therapeutic intervention in alkali injured eyes.

Keywords: NLRP3 inflammasome; alkali injury; sodium butyrate; β-hydroxybutyric acid.

MeSH terms

  • Alkalies / toxicity
  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Burns, Chemical / drug therapy*
  • Burns, Chemical / metabolism
  • Butyrates / pharmacology
  • Butyrates / therapeutic use*
  • CARD Signaling Adaptor Proteins
  • Caspase 1 / metabolism
  • Cornea / drug effects
  • Cornea / metabolism
  • Corneal Injuries / chemically induced
  • Corneal Injuries / drug therapy*
  • Corneal Injuries / metabolism
  • Eye Burns / chemically induced
  • Eye Burns / drug therapy*
  • Eye Burns / metabolism
  • Female
  • Inflammasomes / metabolism*
  • Interleukin-1beta / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Wound Healing / drug effects*


  • Alkalies
  • Apoptosis Regulatory Proteins
  • Butyrates
  • CARD Signaling Adaptor Proteins
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Pycard protein, mouse
  • Caspase 1